CEP76 impairment at the centrosome-cilium interface contributes to a spectrum of ciliopathies.

Dysfunction at the centrosome-cilium interface underlies a broad range of ciliopathies. Here, we identify biallelic variants in CEP76, encoding a centrosomal protein, in eight unrelated individuals presenting with neurodevelopmental, ocular, and variable additional multisystem features. Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits, including impaired cilium formation and length, disrupted transition zone architecture, and impaired IFT88-mediated anterograde intraflagellar transport. Zebrafish cep76 mutants recapitulate key clinical phenotypes, and in vitro complementation assays confirm pathogenicity for all tested human disease-associated variants. Proteomics analysis identifies CEP76 interactors, including known partners CCP110 and CEP97, and highlights clinically and functionally relevant candidates, including ALMS1 and LUZP1. Together, these findings expand the role of CEP76 beyond centriole duplication to include ciliary assembly and trafficking, establishing it as a ciliopathy gene. This work provides mechanistic insights into CEP76-related disease and broadens our understanding of centrosome-cilium biology.